Retrospective analysis of Tripterygium wilfordii polyglycoside combined with angiotensin receptor blockers for the treatment of primary membranous nephropathy with sub-nephrotic proteinuria

Figures & data

Figure 1. Flow diagram of patient enrollment. TWG: Tripterygium wilfordii polyglycoside; ARB: angiotensin receptor blocker.

Table 1. Baseline characteristics of patients.

Variable	Normal ranges	TWG + ARB	ARB	p Value
No. patients		35	20
Age (yr)		49.89 ± 9.20	44.47 ± 12.23	0.118
Gender (M/F)		20/15	11/9
Blood pressure (mmHg)
Systolic pressure		126.74 ± 12.52	126.76 ± 8.96	0.995
Diastolic pressure		81.80 ± 8.66	78.71 ± 6.76	0.202
Hb (g/L)	130–175	131.74 ± 18.16	131.12 ± 8.31	0.865
TG (mmol/L)	<1.7	2.21 ± 1.22	1.80 ± 0.55	0.096
TC (mmol/L)	<5.2	6.86 ± 1.84	6.70 ± 1.82	0.081
SAlb (g/L)	35–55	26.89 ± 5.82	26.79 ± 4.88	0.951
Scr (μmol/L)	20–115	64.29 ± 14.25	58.47 ± 13.21	0.164
BUN (μmol/L)	2.2–8.2	4.55 ± 1.19	4.53 ± 0.78	0.936
UA (μmol/L)	200–440	290.74 ± 66.96	325.24 ± 67.44	0.088
ALT (U/L)	0–40	23.26 ± 17.17	17.47 ± 7.04	0.092
AST (U/L)	0–40	24.46 ± 8.99	21.76 ± 4.41	0.153
eGFR (mL/min/1.73m^2)		101.42 ± 19.14	109.82 ± 15.57	0.122
Histology grading of IMN
Stage I		5	6
Stage I–II		9	4
Stage II		14	7
Stage II–III		5	2
Stage III		2	1
Urine protein (g/24hr)	0–0.15	2.59 ± 0.46	2.30 ± 0.34	0.307
Anti-PLA2R (RU/ml)	0–14	53 (13.70,86.70)	58.55 (10.8,101.6)	0.746

Values are means ± SD, medians (interquartile range), or number of patients; Hb: Hemoglobin; TG: Triglyceride; TC: Total cholesterol; ALT: alanine transaminase; AST: aspartate aminotransferase; Scr: serum creatinine; BUN: blood urea nitrogen; eGFR: estimated glomerular filtration rate; PMN: primary membranous nephropathy; TWG: tripterygium wilfordii polyglycoside; ARB: Angiotensin Receptor Blockers; Anti-PLA₂R: antibody against m-type phospholipase A2 receptor. As non-normally distributed data, anti-PLA₂R are presented as the median with interquartile range and are analyzed using the Mann-Whitney U test.

Table 2. Baseline Characteristics of anti-PLA2R-positive patients.

Variable	Normal ranges	TWG + ARB	ARB	p Value
No. patients		26	14
Age (yr)		49.0 ± 9.13	44.79 ± 11.29	0.208
Gender (M/F)		16/10	9/5
Blood pressure (mmHg)
Systolic pressure		129.92 ± 12.06	127.5 ± 9.17	0.516
Diastolic pressure		83.04 ± 8.37	78.57 ± 8.11	0.112
Hb (g/L)	130–175	135.31 ± 16.72	131.21 ± 7.85	0.424
TG (mmol/L)	<1.7	2.34 ± 1.34	1.84 ± 0.58	0.105
TC (mmol/L)	<5.2	7.15 ± 1.90	7.01 ± 0.95	0.797
SAlb (g/L)	35–55	27.06 ± 6.16	27.89 ± 3.77	0.651
Scr (μmol/L)	20–115	65.73 ± 15.54	61.71 ± 13.91	0.424
BUN (μmol/L)	2.2–8.2	4.79 ± 1.23	4.39 ± 0.67	0.189
UA (μmol/L)	200–440	299.42 ± 64.16	314.14 ± 63.39	0.491
ALT (U/L)	0–40	21.92 ± 17.22	17.50 ± 7.29	0.367
AST (U/L)	0–40	23.65 ± 8.48	22.29 ± 3.73	0.571
eGFR (mL/min/1.73m^2)		100.72 ± 21.47	110.74 ± 15.33	0.131
Histology grading of IMN
Stage I		3	6
Stage I-II		7	2
Stage II		11	4
Stage II-III		4	2
Stage III		1	0
Urine protein (g/24hr)	0–0.15	2.49 ± 0.91	2.21 ± 0.85	0.353
Anti-PLA2R (RU/ml) (+)	0–14	73.65 (37.18,123.50)	61.38 (55.08,157.68)	0.834

Figure 2. Percentage of complete and partial remissions in the TWG + ARB and ARB therapy groups. ^#shows that the remission rate was significantly greater in the TWG + ARB group compared to the ARB group during the treatment (p < 0.05). TWG: Tripterygium wilfordii polyglycoside; ARB, angiotensin receptor blocker.

Figure 3. Kaplan-Meier curves for probability of overall remission for the TWG + ARB and ARB therapy groups. TWG: Tripterygium wilfordii polyglycoside; ARB: angiotensin receptor blocker; PLA2R, phospholipase A2 receptor.

Figure 4. The changes of serum albumin (A) and proteinuria (B) in the TWG + ARB and ARB therapy groups. (A)*^&statistically a significant elevation of serum albumin between the end of treatment and baseline in the TWG + ARB group and ARB group (P < 0.01); ^$comparing to ARB group, the TWG + ARB group showed more obvious elevation of albumin level in 6 months and 9 months (p = 0.021, p = 0.001). TWG: Tripterygium wilfordii polyglycoside; ARB: angiotensin receptor blocker. (B)*^&statistically a significant reduction of proteinuria between the end of treatment and baseline in the TWG + ARB group and ARB group (p < 0.01); ^#The reduction of daily proteinuria after 6 and 9 months of treatment were more obvious in the TWG + ARB group (p = 0.008, p = 0.001). TWG: Tripterygium wilfordii polyglycoside; ARB: angiotensin receptor blocker

Figure 5. Responses of patients who were positive or negative for anti-PLA2R antibodies during follow-up. TWG: Tripterygium wilfordii polyglycoside; ARB: angiotensin receptor blocker; PLA2R: phospholipase A2 receptor.

Figure 6. Responses of patients who were positive or negative for anti-PLA2R antibodies during follow-up. ^#shows that the remission rate was significantly greater in the TWG + ARB group compared to the ARB group among patients with anti-PLA2R positive (P < 0.05). TWG: Tripterygium wilfordii polyglycoside; ARB: angiotensin receptor blocker

Figure 7. The variation of anti-PLA2R level in the TWG + ARB and ARB therapy groups. *^&statistically a significant reduction of anti-PLA2R level between the start and end of treatment in the TWG + ARB group and ARB group (p < 0.01); ^$comparing to ARB group, the mean anti-PLA2R levels after 6 and 9 months of treatment were significantly lower in the TWG + ARB group (p = 0.016, p = 0.005). TWG: Tripterygium wilfordii polyglycoside; ARB: angiotensin receptor blocker.

Table 3. Remission rates and p value of the TWG + ARB group compared to ARB group.

Group	Month	TWG + ARB (n = 35)	ARB(n = 20)	p Value
CR + PR	3th	57.1% (20)	10% (2)	0.001
	6th	68.6% (24)	20% (4)	0.001
	9th	74.3% (26)	35% (7)	0.004
CR	3th	17.1% (6)	5% (1)	0.379
	6th	31.4% (11)	10% (2)	0.142
	9th	45.7% (16)	15% (3)	0.044

CR: complete remission; PR: partial remission.

Table 4. Laboratory parameters during the treatment of the two groups.

Variables	TWG + ARB (n = 35)	ARB (n = 20)	p Value
Proteinuria, g/24h
Baseline	2.59 ± 0.46	2.38 ± 0.64	0.497
1mo	2.06 ± 0.59	2.30 ± 0.58	0.520
3mo	1.71 ± 0.44	2.24 ± 0.54	0.110
6mo	1.17 ± 0.57	2.14 ± 0.59	0.005
9mo	0.57 ± 0.61	1.80 ± 0.67	0.001
Serum albumin level, g/l
Baseline	26.89 ± 5.82	26.79 ± 4.88	0.951
1mo	27.88 ± 4.78	27.64 ± 5.13	0.867
3mo	29.35 ± 5.40	28.36 ± 5.22	0.509
6mo	32.89 ± 5.80	29.38 ± 5.41	0.037
9mo	36.27 ± 3.39	31.69 ± 4.64	0.001
eGFR (mL/min/1.73m^2)
Baseline	101.42 ± 19.14	109.82 ± 15.57	0.122
1mo	99.83 ± 18.72	108.99 ± 13.93	0.163
3mo	97.96 ± 19.63	98.36 ± 12.34	0.213
6mo	100.23 ± 17.96	101.49 ± 19.37	0.121
9mo	98.36 ± 19.21	104.37 ± 18.33	0.415

Table 5. Predictor variables related to survival to the outcome of progression of renal disease (assessed as complete remission) at the multivariable Cox regression analysis.

Parameter	p Value	HR	95% CI
Age	0.880	0.914	0.285,2.932
Gender	0.578	0.774	0.313,1.911
Anti-PLA2R at baseline	0.066	3.979	0.913,7.337
Treatment group (TWG + ARB vs ARB)	0.048	0.274	0.0760,0.991

CI, confidence intervals; HR, hazard ratio.

Table 6. Adverse events.

Adverse effects	TWG + ARB (n = 35)	ARB (n = 20)
Liver dysfunction	3 (8.6%)	1 (5%)
Hypotension	0	2 (10%)
Leukopenia	0	0
Anemia	0	0
Irregular menstruation	2 (5.8%)	0